DNA Cleavage Properties, Antimicrobial and Cytotoxic Activity and 4D-QSAR Analysis of Some Pyrazole Derivatives

Author(s): Semiha Kopru, Fatma Ozturk Küp*, Nazmiye Sabanci, Mehmet Çadir, Duygu Cemre Bulut, Fatih Duman, Ilhan Ozer İlhan, Emin Saripinar*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 8 , 2019

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Graphical Abstract:


Background: An extensive study of 19 pyrazole derivatives were carried out based on the evaluation of DNA cleavage properties, antimicrobial and cytotoxic activities and 4D-QSAR analysis including pharmacophore modelling and bioactivity prediction by the Electron Conformational-Genetic Algorithm (EC-GA) method.

Methods: The pyrazole derivatives were tested for their antimicrobial activity against certain human pathogenic organisms using the agar diffusion procedure. Binding of compounds with DNA was studied by gel electrophoresis using plasmid pBR322 DNA. The compounds were investigated for their properties as cytotoxic agents by brine shrimp lethality bioassay. To identify the pharmacophoric elements and find out the most important molecular properties which govern cytotoxic activity, multiple conformations of the compounds were used.

Results: The urea derivatives of pyrazole had higher antibacterial activities against Gram-negative bacteria than against Gram-positive bacteria. Many of the compounds were found to cleave plasmid pBR322 DNA from the supercoiled form to the nicked circular. The cytotoxicity values of the compounds ranged from 13.87 to 84.1 µg/mL. The generated QSAR model was evaluated through the use of the Leave-One-Out Cross Validation (LOO-CV) method. A statistically significant and considerably predictive QSAR model was obtained with 4- descriptors resulting in R2 training =0.8223, R2 test =0.9346, q2=0.6201, q2 ext1=0.8672, q2 ext2= 0.8662 and q2 ext3=0.9511.

Discussion: The generated model demonstrates that geometrical parameters are more correlated with cytotoxic activity. The resulting EC-GA model would provide benefits to design novel bioactive pyrazole derivatives which are more potent and have less side effects.

Conclusion: It is believed that the generated QSAR model gives insight into developing new more potent pyrazole derivative drugs.

Keywords: DNA cleavage, antimicrobial activity, cytotoxic activity, EC-GA method, 4D-QSAR, pyrazole.

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Article Details

Year: 2019
Page: [904 - 918]
Pages: 15
DOI: 10.2174/1570180815666180926104319
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